Functional Substitution by TAT-Utrophin in Dystrophin-Deficient Mice

James Ervasti and colleagues show that injection of a truncated form of utrophin transduced all tissues examined, integrated with members of the dystrophin complex, and reduced serum levels of creatine kinase in a mouse model of muscular dystrophy

Differential impact of Met receptor gene interaction with early-life stress on neuronal morphology and behavior in mice

Early adversity in childhood increases the risk of anxiety, mood, and post-traumatic stress disorders in adulthood, and specific gene-by-environment interactions may increase risk further. A common functional variant in the promoter region of the gene encoding the human MET receptor tyrosine kinase (rs1858830 ‘C’ allele) reduces expression of MET and is associated with altered cortical circuit function and structural connectivity. Mice with reduced Met expression exhibit changes in anxiety-like and conditioned fear behavior, precocious synaptic maturation in the hippocampus, and reduced neuronal arbor complexity and synaptogenesis. These phenotypes also can be produced independently by early adversity in wild-type mice. The present study addresses the outcome of combining early-life stress and genetic influences that alter timing of maturation on enduring functional and structural phenotypes. Using a model of reduced Met expression (Met+/−) and early-life stress from postnatal day 2–9, social, anxiety-like, and contextual fear behaviors in later life were measured. Mice that experienced early-life stress exhibited impairments in social interaction, whereas alterations in anxiety-like behavior and fear learning were driven by Met haploinsufficiency, independent of rearing condition. Early-life stress or reduced Met expression decreased arbor complexity of ventral hippocampal CA1 pyramidal neurons projecting to basolateral amygdala. Paradoxically, arbor complexity in Met+/− mice was increased following early-life stress, and thus not different from arbors in wild-type mice raised in control conditions. The changes in dendritic morphology are consistent with the hypothesis that the physiological state of maturation of CA1 neurons in Met+/− mice influences their responsiveness to early-life stress. The dissociation of behavioral and structural changes suggests that there may be phenotype-specific sensitivities to early-life stress. Keywords: Early-life stress, Gene × environment interaction, MET receptor tyrosine kinase, Social-emotional behavior, Neuronal morpholog

Using dynamic microsimulation to project cognitive function in the elderly population.

BackgroundA long-term projection model based on nationally representative data and tracking disease progression across Alzheimer's disease continuum is important for economics evaluation of Alzheimer's disease and other dementias (ADOD) therapy.MethodsThe Health and Retirement Study (HRS) includes an adapted version of the Telephone Interview for Cognitive Status (TICS27) to evaluate respondents' cognitive function. We developed an ordered probit transition model to predict future TICS27 score. This transition model is utilized in the Future Elderly Model (FEM), a dynamic microsimulation model of health and health-related economic outcomes for the US population. We validated the FEM TICS27 model using a five-fold cross validation approach, by comparing 10-year (2006-2016) simulated outcomes against observed HRS data.ResultsIn aggregate, the distribution of TICS27 scores after ten years of FEM simulation matches the HRS. FEM's assignment of cognitive/mortality status also matches those observed in HRS on the population level. At the individual level, the area under the receiver operating characteristic (AUROC) curve is 0.904 for prediction of dementia or dead with dementia in 10 years, the AUROC for predicting significant cognitive decline in two years for mild cognitive impairment patients is 0.722.ConclusionsThe FEM TICS27 model demonstrates its predictive accuracy for both two- and ten-year cognitive outcomes. Our cognition projection model is unique in its validation with an unbiased approach, resulting in a high-quality platform for assessing the burden of cognitive decline and translating the benefit of innovative therapies into long-term value to society

Geographic differences in the mortality burden of the Covid-19 pandemic

This study examines how the mortality burden of the Covid-19 pandemic varied across US states during the time period April 2020 through December 2022. The disparities were substantial, with figures ranging from 318 years of life lost (YLL) per 10,000 population in New York to 1,285 YLL per 10,000 population in New Mexico. Illinois experienced a loss of 588 YLL per 10,000, situating it within the bottom third of states in terms of total loss of life. Overall, Southern and Western states exhibited the highest YLL, while Northeastern states, the upper Midwest, and the Pacific Northwest exhibited the lowest YLL. States that voted for the 2020 Republican presidential candidate experienced greater losses. This loss of life will have multifaceted implications for public finances.</p